Clinical, splicing and functional analysis to classify BRCA2 exon 3 variants

Autor: Thomassen, M., Mesman, R.L.S., Hansen, T.V.O., Menendez, M., Rossing, M., Esteban-Sanchez, A., Tudini, E., Torngren, T., Parsons, M.T., Pedersen, I.S., Teo, S.H., Kruse, T.A., Moller, P., Borg, A., Jensen, U.B., Christensen, L.L., Singer, C.F., Muhr, D., Santamarina, M., Brandao, R., Andresen, B.S., Feng, B.J., Canson, D., Richardson, M.E., Karam, R., Pesaran, T., LaDuca, H., Conner, B.R., Abualkheir, N., Hoang, L., Calleja, F.M.G.R., Andrews, L., James, P.A., Bunyan, D., Hamblett, A., Radice, P., Goldgar, D.E., Walker, L.C., Engel, C., Claes, K.B.M., Machackova, E., Baralle, D., Viel, A., Wappenschmidt, B., Lazaro, C., Vega, A., Vreeswijk, M.P.G., Hoya, M. de la, Spurdle, A.B., ENIGMA Consortium
Přispěvatelé: RS: GROW - R4 - Reproductive and Perinatal Medicine, Klinische Genetica
Jazyk: angličtina
Rok vydání: 2022
Předmět:
Zdroj: HUMAN MUTATION
Human Mutation: Variation, Informatics and Disease, 43(12), 1921-1944. WILEY-HINDAWI
Thomassen, M, Mesman, R L S, Hansen, T V O, Menendez, M, Rossing, M, Esteban-Sánchez, A, Tudini, E, Törngren, T, Parsons, M T, Pedersen, I S, Teo, S H, Kruse, T A, Møller, P, Borg, Å, Jensen, U B, Christensen, L L, Singer, C F, Muhr, D, Santamarina, M, Brandao, R, Andresen, B S, Feng, B-J, Canson, D, Richardson, M E, Karam, R, Pesaran, T, LaDuca, H, Conner, B R, Abualkheir, N, Hoang, L, Calléja, F M G R, Andrews, L, James, P A, Bunyan, D, Hamblett, A, Radice, P, Goldgar, D E, Walker, L C, Engel, C, Claes, K B M, Macháčková, E, Baralle, D, Viel, A, Wappenschmidt, B, Lazaro, C, Vega, A, Vreeswijk, M P G, de la Hoya, M, Spurdle, A B & ENIGMA Consortium 2022, ' Clinical, splicing, and functional analysis to classify BRCA2 exon 3 variants : Application of a points-based ACMG/AMP approach ', Human Mutation, vol. 43, no. 12, pp. 1921-1944 . https://doi.org/10.1002/humu.24449
Thomassen, M, Mesman, R L S, Hansen, T V O, Menendez, M, Rossing, M, Esteban-Sánchez, A, Tudini, E, Törngren, T, Parsons, M T, Pedersen, I S, Teo, S H, Kruse, T A, Møller, P, Borg, Å, Jensen, U B, Christensen, L L, Singer, C F, Muhr, D, Santamarina, M, Brandao, R, Andresen, B S, Feng, B J, Canson, D, Richardson, M E, Karam, R, Pesaran, T, LaDuca, H, Conner, B R, Abualkheir, N, Hoang, L, Calléja, F M G R, Andrews, L, James, P A, Bunyan, D, Hamblett, A, Radice, P, Goldgar, D E, Walker, L C, Engel, C, Claes, K B M, Macháčková, E, Baralle, D, Viel, A, Wappenschmidt, B, Lazaro, C, Vega, A, Vreeswijk, M P G, de la Hoya, M, Spurdle, A B & ENIGMA Consortium 2022, ' Clinical, splicing, and functional analysis to classify BRCA2 exon 3 variants : Application of a points-based ACMG/AMP approach ', Human Mutation, vol. 43, no. 12, pp. 1921-1944 . https://doi.org/10.1002/humu.24449
Human Mutation, 43(12), 1921-1944. Wiley
Thomassen, M, Mesman, R L S, Hansen, T V O, Menendez, M, Rossing, M, Esteban-Sánchez, A, Tudini, E, Törngren, T, Parsons, M T, Pedersen, I S, Teo, S H, Kruse, T A, Møller, P, Borg, Å, Jensen, U B, Christensen, L L, Singer, C F, Muhr, D, Santamarina, M, Brandao, R, Andresen, B S, Feng, B-J, Canson, D, Richardson, M E, Karam, R, Pesaran, T, LaDuca, H, Conner, B R, Abualkheir, N, Hoang, L, Calléja, F M G R, Andrews, L, James, P A, Bunyan, D, Hamblett, A, Radice, P, Goldgar, D E, Walker, L C, Engel, C, Claes, K B M, Macháčková, E, Baralle, D, Viel, A, Wappenschmidt, B, Lazaro, C, Vega, A, ENIGMA consortium, Vreeswijk, M P G, de la Hoya, M & Spurdle, A B 2022, ' Clinical, splicing and functional analysis to classify BRCA2 exon 3 variants : application of a points-based ACMG/AMP approach ', Human Mutation, vol. 43, no. 12, pp. 1921-1944 . https://doi.org/10.1002/humu.24449
ISSN: 1059-7794
1098-1004
DOI: 10.1002/humu.24449
Popis: Skipping of BRCA2 exon 3 (∆E3) is a naturally occurring splice event, complicating clinical classification of variants that may alter ∆E3 expression. This study used multiple evidence types to assess pathogenicity of 85 variants in/near BRCA2 exon 3. Bioinformatically predicted spliceogenic variants underwent mRNA splicing analysis using minigenes and/or patient samples. ∆E3 was measured using quantitative analysis. A mouse embryonic stem cell (mESC) based assay was used to determine the impact of 18 variants on mRNA splicing and protein function. For each variant, population frequency, bioinformatic predictions, clinical data and existing mRNA splicing and functional results were collated. Variant class was assigned using a gene-specific adaptation of ACMG/AMP guidelines, following a recently proposed points-based system. mRNA and mESC analysis combined identified six variants with transcript and/or functional profiles interpreted as loss of function. Cryptic splice site use for acceptor site variants generated a transcript encoding a shorter protein that retains activity. Overall, 69/85 (81%) variants were classified using the point-based approach. Our analysis shows the value of applying gene-specific ACMG/AMP guidelines using a points-based approach and highlights the consideration of cryptic splice site usage to appropriately assign PVS1 code strength. This article is protected by copyright. All rights reserved.
Databáze: OpenAIRE
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